Iodohydroxylation of olefins

ABSTRACT

Iodohydroxylated olefins can be prepared by treating an olefin with an aqueous solution of an iodine monohalide selected from iodine monochloride and iodine monobromide.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/353,643, filed Feb. 1, 2002.

FIELD OF THE INVENTION

[0002] The present invention is directed to the iodohydroxylation ofolefins using aqueous iodine monochloride or aqueous iodine monobromide.

BACKGROUND OF THE INVENTION

[0003] Iodohydrins are useful as intermediates in the preparation ofpharmaceutically active compounds. For example, U.S. Pat. No. 5,728,840and WO 01/38332 disclose iodohydrins which are useful as intermediatesin the preparation of HIV protease inhibitors. Another example is WO95/16658, which discloses the use of iodohydrins in the preparation ofallylic halides that are intermediates for the synthesis of antifungalagents. Iodohydrins are also useful in the preparation ofbisperfluoroalkyldiols as described in U.S. Pat. No. 5,708,119, whereinthe bisperfluoroalkyldiols and their derivatives can impart oil andwater repellancy to various materials such as glass, wood, paper,leather, wool, cotton and polyester. Iodohydrins have been prepared fromolefins by a variety of methods. Ohta et al., Chem. Letters 1990,733-736 reports the synthesis of iodohydrins from certain alkenes,alkenols, and alkenones by treatment with periodic acid (H₅IO₆) andsodium bisulfite (NaHSO₃) under mild conditions. Masuda et al., J. Org.Chem. 1994, 59: 5550-5555 provides further details on the preparation ofiodohydrins using H₅IO₆+NaHSO₃.

[0004] Sanseverino et al., Synthesis 1998 11: 1584-1586 discloses thepreparation of β-iodo ethers and iodohydrins in relatively good yieldsby the reaction of alcohols and water respectively with alkenes in thepresence of molecular iodine. The use of molecular iodine leads to theformation of HI during the reaction which in turn causes the reactionmixture to become increasingly acidic. This can trigger side reactionsfor acid sensitive reactions such as iodohydroxylation of2-alkyl-4-enamides, as described in Maligres et al., Tetrahedron Letters1995, 36: 2195. Furthermore, the presence of iodide can triggeradditional side reactions as, for example, described in Sun et al,Tetrahedron Letters 2001, 42: 8603.

[0005] De Corso et al., Tetrahedron Letters 2001, 42; 7245-7247discloses the iodohydroxylation of various olefins by treatment with amixture of molecular iodine and phenyliodine(III)bis(trifluoroacetate)in acetonitrile-H₂O solvent. The drawbacks of this approach include theuse of molecular iodine (see preceding paragraph) and the expense of thetrifluoroacetate oxidant. Asensio et al., Org. Lett. 1999, 1: 2125-2128describes the formation of iodohydrins by the oxidation of iodomethanewith dimethyldioxirane (DMDO) in acetone at −70° C., followed byaddition of an olefin and slow warming of the mixture to roomtemperature. Unfortunately, very low temperatures are required due tothe thermal instability of the reaction system. In addition, DMDO is arelatively expensive reagent.

[0006] U.S. Pat. No. 5,728,840 discloses the iodohydroxylation of anallyl acetonide by treating allyl acetonide 1 with N-iodosuccinimide(NIS) and aqueous sodium bicarbonate to provide iodohydrin 2, which isan intermediate in the preparation of indinavir, an HIV proteaseinhibitor:

[0007] Although NIS is a practical iodohydroxylation reagent, it becomesincreasingly unstable above a pH of 8 and loses its ability toiodohydroxylate due to rapid decomposition. U.S. Pat. No. 5,981,759discloses the iodohydroxylation of allyl acetonide 1 to provideiodohydrin 2 by treating the acetonide with an aqueous solution ofalkali metal hypohalite (e.g., NaOCl) and an aqueous solution of analkali halide (e.g., NaI). While this process is characterized by highyields, operability over a wide pH range, and minimal production oforganic wastes, it does exhibit a mixing sensitivity (i.e., the level ofconversion decreases with increasing mixing intensity). This mixingsensitivity can present a problem during process scaleup, because mixingintensity in large vessels will vary from vessel to vessel, and can besignificantly higher than that employed in typical, small-scalelaboratory vessels. The process also requires two addition lines, onefor the hypohalite solution and one for the halide solution, tointroduce the iodohydroxylation reagent.

SUMMARY OF THE INVENTION

[0008] The present invention is an improved process for the preparationof iodohydroxylated olefins. More particularly, the present invention isa process for preparing an iodohydroxylated olefin which comprisestreating an olefin with an aqueous solution of an iodine monohalideselected from iodine monochloride (ICI) and iodine monobromide (IBr).While not wishing to be bound by theory, it is believed that hypoiodousacid (HOI) is the active agent in the process of the invention and israpidly and cleanly generated in situ via hydrolysis of ICI or IBr toprovide for efficient iodohydroxylation of the olefin. The process ofthe invention can be operated over a relatively wide range of pH, whichcan be adjusted to and maintained at (i.e., “tuned” to) a value thatoptimizes yield of the desired iodohydroxylated product andconcomitantly minimizes or suppresses by-product formation. In addition,and in contrast with the NaOCl/NaI process of U.S. Pat. No. 5,981,759(see Background), the process of the invention is relatively insensitiveto the degree of mixing/agitation of the reaction mixture; i.e., theconversion of olefin to iodohydrin exhibits little or no dependence onmixing intensity over a wide range of intensities. Further in contrastwith the NaOCl/NaI process of U.S. Pat. No, '759, the process of theinvention utilizes only one addition line (instead of two) for theiodohydroxylation reagent, which can reduce equipment complexity andcosts.

[0009] Various embodiments, aspects and features of the presentinvention are either further described in or will be apparent from theensuing description, examples, and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The iodine monohalide can be iodine monochloride (ICI) or iodinemonobromide (IBr). In one embodiment, the iodine monohalide is ICI.

[0011] The olefin reactant employed in the process of the invention canbe any organic compound which contains at least one carbon-carbon doublebond. Suitable olefin reactants include, but are not limited to,aliphatic hydrocarbon mono-olefins (e.g., alkenes such as propylene,1-butene, 2-butene, isobutene, 1-pentene, 2-pentene,2,3-dimethyl-2-butene, and the like) and diolefins (e.g., alkadienessuch as 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene,and the like), alicyclic hydrocarbon olefins (e.g., cycloalkenes such ascyclopentene, cyclohexene, cycloheptene, cyclooctene, and the like) anddiolefins (e.g., cycloalkadienes such as cyclopentadiene,cyclohexadiene, cyclooctadiene, and the like), mono- and di-unsaturatedbicyclic hydrocarbons (e.g., norbornene, norbornadiene,1,4-dihydronaphthalene, and indene), and alkenyl substituted aromatichydrocarbons (e.g., styrene, α-methylstyrene, α-ethylstyrene,1-ethenyl-2-methylbenzene, 1-ethenyl-2,6-dimethylbenzene,1-ethenyl-2,5-dimethylbenzene, 1-phenyl-1-propylethylene,1-phenyl-1-n-butylethylene, 1-phenyl-1-n-pentylethylene, 1-phenyl-1-n-hexylethylene, 1-phenyl-1-isopropylethylene,1-phenyl-1-tert-butylethylene, 1-phenyl-1-cyclopropylethylene,1-phenyl-1-cyclobutylethylene, 1-phenyl-1-cyclopentylethylene,1-phenyl-1-cyclohexylethylene, trans-1-phenyl-2-methylethylene,cis-1-phenyl-2-methylethylene, 1-phenyl-2,2,-dimethylethylene,1-methylene-1,2,3,4-tetrahydronaphthalene,1-methylene-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene).

[0012] Suitable olefin reactants also include, but are not limited to,unsaturated aliphatic and alicyclic halides, carboxylic acids andesters, amines, ethers, alcohols, mercaptans, aldehydes, ketones,sulfones, and alcohols. Among the suitable olefins, for example, arelinear and branched alkenes and alkadienes substituted with a functionalgroup selected from halo, hydroxy (—OH), mercapto (—SH), oxo (═O),alkoxy (—O—C₁₋₁₀ alkyl), primary amino (—NH₂), N-alkylamino(—NH—C₁ alkyl), N,N-dialkylamino (—N(C₁₋₁₀ alkyl)₂), carboxamido(—C(═O)NH₂), carboxy (—COOH), alkoxycarbonyl (—C(═O)O—C₁₋₁₀ alkyl),alkylcarbonyl (—C(═O)—C₁₋₁₀ alkyl), formyl (—CHO), nitro (—NO2), andcyano (—CN).

[0013] Other olefin compounds suitable for use in the present inventioninclude, but are not limited to, acrylic esters such as the alkyl estersof acrylic acid (e.g., methyl acrylate and ethyl acrylate) andmethacrylic acid (methyl methacrylate and ethyl methacrylate). Suitableolefin compounds also include cinnamic acid and esters thereof (e.g.,methyl cinnamate, ethyl cinnamate, n-propyl cinnamate, isopropylcinnamate, phenyl cinnamate, and benzyl cinnamate). Still other suitableolefin compounds include unsaturated fatty acids and fatty acid esterssuch as oleic acid, linoleic acid, a-linoleic acid, erucic acid,arachidonic acid, ricinoleic acid, and esters (e.g., methyl esters)thereof.

[0014] In one embodiment, the olefin reactant is an olefin is of Formula(I):

[0015] wherein each of R¹, R², R³ and R⁴ is independently:

[0016] (1) —H,

[0017] (2) —CO₂R^(a),

[0018] (3) —C(═O)R^(a),

[0019] (4) —C(═O)N(R^(a)R^(b)),

[0020] (5) —CN,

[0021] (6) C₁₋₂₀ alkyl,

[0022] (7) C₂₋₂₀ alkenyl,

[0023] (8) C₃₋₈ cycloalkyl,

[0024] (9) C₅₋₈ cycloalkenyl,

[0025] (10) aryl, or

[0026] (11) heterocycle,

[0027] (12) C₁₋₂₀ alkyl substituted with from 1 to 3 substituents eachof which is independently C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, aryl, orheterocycle,

[0028] (13) C₂₋₂₀ alkenyl substituted with from 1 to 3 substituents eachof which is independently C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, aryl, orheterocycle,

[0029] (14) C₁₋₂₀ alkyl substituted with —C(═O)-aryl or—C(═O)-heterocycle, or

[0030] (15) C₂₋₂₀ alkenyl substituted with —C(═O)-aryl or—C(═O)-heterocycle;

[0031] wherein the alkyl in (6) or (12) or (14) or the alkenyl in (7) or(13) or (15) is optionally substituted with one or more substituents(e.g., from 1 to 8, or 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to3, or 1 or 2 substituents; or is mono-substituted) each of which isindependently halogen, —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), ≧N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), N(R^(a))C(═O)—N(R^(a)R^(b)), —C(═O)—C₁₋₆alkyl-N(R^(a)R^(b)), N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),—N(R^(a))SO₂R^(b), or —SO₂N(R^(a)R^(b));

[0032] wherein the cycloalkyl in (8) or (12) or (13), the cycloalkenyl(9) or (12) or (13), or the aryl in (10) or (12) or (13) or (14) or (15)is optionally substituted with one or more substituents (e.g., from 1 to6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or ismono-substituted) each of which is independently halogen, —OH, —CN,—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)), phenyl, —C₁₋₆alkyl-phenyl, HetA, or —C₁₋₆ alkyl-HetA; and

[0033] wherein the heterocycle (11) or (12) or (13) or (14) or (15) isoptionally substituted with one or more substituents (e.g., from 1 to 6,or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or ismono-substituted) each of which is independently halogen, —OH, —CN,—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)), phenyl, —C₁₋₆alkyl-phenyl, —C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, or oxo;

[0034] or alternatively R¹ and R³ are each independently as definedabove, and R² and R⁴ together with each of the carbon atoms of thecarbon-carbon double bond form C₅₋₁₀ cycloalkenyl or C₅₋₁₀cycloalkadienyl, either of which is optionally substituted with one ormore substituents (e.g., from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3,or 1 or 2 substituents; or is mono-substituted) each of which isindependently halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, or hydroxy; or alternatively R¹ and R² are eachindependently as defined above, and R³ and R⁴ together with the carbonatom of the carbon-carbon double bond to which they are both attachedform C₅₋₁₀ cycloalkyl or C₅₋₁₀ cycloalkenyl, either of which isoptionally substituted with one or more substituents (e.g., from 1 to 6,or 1 to 5, or 1 to 4, or I to 3, or 1 or 2 substituents; or ismono-substituted) each of which is independently halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl or hydroxy;

[0035] each aryl is independently (i) an aromatic carbocyclic ringoptionally substituted with 1 or 2 other aromatic carbocyclic rings or(ii) an aromatic carbocyclic fused ring system optionally substitutedwith 1 or 2 aromatic carbocyclic rings;

[0036] each heterocycle is independently (i) a 4- to 8-membered,saturated or unsaturated monocyclic ring, (ii) a 7- to 12-memberedbicyclic ring system, or (iii) an 11 to 16-membered tricyclic ringsystem; wherein each ring in (ii) or (iii) is independent of or fused tothe other ring or rings and each ring is saturated or unsaturated; themonocyclic ring, bicyclic ring system, or tricyclic ring system containsfrom 1 to 6 heteroatoms independently selected from N, O and S;

[0037] each HetA is independently:

[0038] (i) a 4- to 7-membered saturated heterocyclic ring containingfrom 1 to 4 heteratoms selected from N, O and S, wherein the saturatedheterocyclic ring is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, oroxo, or

[0039] (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to4 heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from 1 to 3substituents each of which is independently halogen, —C₁₋₄ alkyl, or—O—C₁₋₄ alkyl;

[0040] each n is an integer independently equal to zero, 1 or 2; and

[0041] each R^(a) and R^(b) is independently —H or —C₁₋₆ alkyl.

[0042] A class of suitable olefin reactants includes the olefins ofFormula (I), wherein each R^(a) and R^(b) is independently —H or —C₁₋₄alkyl; and all other variables are as originally defined. An aspect ofthis class includes olefins of Formula (I), wherein each R^(a) and R^(b)is independently a —C₁₋₄ alkyl group. A sub-class of the preceding classincludes olefins of Formula (I), in which each R^(a) and R^(b) isindependently —H, methyl or ethyl; and all other variables are asoriginally defined. An aspect of this sub-class includes olefins ofFormula (I), in which each R^(a) and R^(b) is independently —H ormethyl. Other aspects of this sub-class include olefins of Formula (I)in which each R^(a) and R^(b) is —H; and in which each R^(a) and R^(b)is methyl.

[0043] A class of suitable olefin reactants includes the aliphatichydrocarbon mono-olefins of Formula (I), wherein each of R¹, R², R³ andR⁴ is independently —H or C₁₋₂₀ alkyl. A sub-class of the aliphatichydrocarbon mono-olefins includes mono-olefins of Formula (I), in whichtwo of R¹, R², R³ and R⁴ are —H, and the other two of R¹, R², R³ and R⁴are each independently —H or C₁₋₂₀ alkyl. Another sub-class of thealiphatic hydrocarbon mono-olefins includes mono-olefins of Formula (I),in which R¹ is —H or C₁₋₂₀ alkyl, and each of R², R³ and R⁴is —H.Another sub-class of the aliphatic hydrocarbon mono-olefins includesmono-olefins of Formula (I), in which R¹ is C₁₋₂₀ alkyl, and each of R²,R³ and R⁴ is —H.

[0044] Another class of suitable olefin reactants includes the aliphatichydrocarbon diolefins of Formula (I), wherein one of R¹, R², R³ and R⁴is C₂₋₂₀ alkenyl, and each of the others of R¹, R², R³ and R⁴isindependently —H or C₁₋₂₀ alkyl. A sub-class of the aliphatichydrocarbon diolefins includes diolefins of Formula (I), in which one ofR¹, R², R³ and R⁴ is C₂₋₂₀ alkenyl, another of R¹, R², R³ and R⁴ isC₁₋₂₀ alkyl, and the remaining two of R¹, R², R³ and R⁴ are —H. Anothersub-class of the aliphatic hydrocarbon diolefins includes diolefins ofFormula (I), in which R¹ is C₂₋₂₀ alkenyl, and each of R², R³ and R⁴ is—H.

[0045] Another class of suitable olefin reactants includes thearyl-substituted aliphatic hydrocarbon mono-olefins of Formula (I),wherein one of R¹, R², R³ and R⁴ is aryl or —C₁₋₂₀ alkyl-aryl; and eachof the others of R¹, R², R³ and R⁴ is —H or C₁₋₂₀ alkyl. A sub-class ofthe aryl-substituted aliphatic hydrocarbon mono-olefins includesmono-olefins of Formula (I), in which one of R¹ and R² is aryl or —C₁₋₁₀alkyl-aryl; the other of R¹ and R² is —H; one of R³ and R⁴ is —H orC₁₋₂₀ alkyl; and the other of R³ and R⁴ is —H. Another sub-class of thearyl-substituted aliphatic hydrocarbon mono-olefins includesmono-olefins of Formula (I), wherein one of R¹ is aryl or —C₁₋₆alkyl-aryl; R² is —H; one of R³ and R⁴ is —H or C₁₋₁₀ alkyl; and theother of R³ and R⁴ is —H.

[0046] Another class of suitable olefin reactants includes thearyl-substituted aliphatic hydrocarbon diolefins of Formula (I), whereinone of R¹, R², R³ and R⁴ is —C₂₋₂₀ alkenyl-aryl; and each of the othersof R¹, R², R³ and R⁴ is —H or C₁₋₂₀ alkyl. A sub-class of thearyl-substituted aliphatic hydrocarbon diolefins includes diolefins ofFormula (I), in which one of R¹ and R² is —C₂₋₁₀ alkenyl-aryl; the otherof R¹ and R² is —H; one of R³ and R⁴ is —H or C₁₋₂₀ alkyl; and the otherof R³ and R⁴ is —H. Another sub-class of the aryl-substituted aliphatichydrocarbon diolefins includes diolefins of Formula (I), in which R¹ is—CH═CH-aryl; R² is —H; one of R³ and R⁴ is —H or C₁₋₁₀ alkyl; and theother of R³ and R⁴ is —H. Another sub-class of the aryl-substitutedaliphatic hydrocarbon diolefins includes diolefins of Formula (I), inwhich R¹ is —CH═CH₂; R² is —H; one of R³ and R⁴ is —C₁₋₁₀ alkyl-aryl;and the other of R³ and R⁴ is —H.

[0047] Another embodiment of suitable olefin reactants includesheterocyclic-containing allyl compounds of Formula (I), wherein R¹, R²,and R³ are all —H; and R⁴ is C₁₋₂₀ alkyl which is:

[0048] (i) optionally substituted with C₃₋₆ cycloalkyl, aryl, or HetB,wherein the cycloalkyl, aryl, or HetB is optionally substituted with oneor more substituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2substituents; or is mono-substituted) each of which is independentlyhalogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆haloalkyl;

[0049] wherein HetB is a 5- or 6-membered heteroaromatic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S; and

[0050] (ii) substituted with —(C═O)-heterocycle, wherein the heterocycleis optionally substituted with one or more substituents (e.g., from 1 to6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or ismono-substituted) each of which is independently halogen, —OH, —C₁₋₆alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋6 haloalkyl.

[0051] A class of the heterocyclyl allyl reactants includes compounds ofFormula (I), wherein R¹, R², and R³ are all —H; and R⁴ is C₁₋₁₀ alkylwhich is (i) substituted with an aryl selected from the group consistingof phenyl and naphthyl and is (ii) substituted with —(C═O)-heterocycle,wherein the heterocycle is optionally substituted with from 1 to 5substituents each of which is independently halogen, —OH, —C₁₋₆ alkyl,—C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl.

[0052] Another class of the heterocyclic-containing allyl reactantsincludes compounds of Formula (II):

[0053] wherein A is absent, CH₂, O, or S;

[0054] R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or HetB;wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB is optionallysubstituted with one or more substituents (e.g., from 1 to 4, or 1 to 3,or 1 or 2 substituents; or is mono-substituted) each of which isindependently halogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or—O—C₁-C₆ haloalkyl;

[0055] HetB in R⁵ is a 5- or 6-membered monocyclic aromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and

[0056] R⁶ and R⁷ are each independently —H, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₃-C₆ cycloalkyl, or aryl, wherein aryl is selected fromphenyl and naphthyl, and is optionally substituted with one or moresubstituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents; oris mono-substituted) each of which is independently halogen, —OH, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; oralternatively

[0057] R⁶ and R⁷ together with the carbons to which each is attachedform a fused benzene ring which is optionally substituted with one ormore substituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents;or is mono-substituted) each of which is independently halogen, —OH,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alky, or —O—C₁-C₆ haloalkyl.

[0058] Another class of the heterocyclic-containing allyl reactantsincludes compounds of Formula (m), (IV), (V), and (VI):

[0059] wherein R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, orHetB; wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB isoptionally substituted with one or more substituents (e.g., from 1 to 4,or 1 to 3, or 1 or 2 substituents; or is mono-substituted) each of whichis independently halogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or—O—C₁-C₆ haloalkyl;

[0060] HetB is as earlier defined;

[0061] R⁶ is —H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl, orphenyl, wherein the phenyl is optionally substituted with one or moresubstituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents; oris mono-substituted) each of which is independently halogen, —OH, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl;

[0062] each Y* is independently —H, halogen, —C₁-C₄ alkyl, —C₁-C₄fluoroalkyl, or —O—C₁-C₄ alkyl; and

[0063] p* is an integer equal to zero, 1 or 2.

[0064] An aspect of the preceding class is an olefin which is:

[0065] Additional embodiments of the present invention include, but arenot limited to, olefins of Formula I wherein each of two or three ormore of R¹, R², R³, R⁴, R^(a), and R^(b) is independently defined inaccordance with its definition in one of the foregoing classes set forthabove or a sub-class or aspect thereof. Any and all possiblecombinations of these variables in Formula I are embodiments within thescope of the present invention.

[0066] Unless expressly stated to the contrary, all ranges cited hereinare inclusive. For example, a heteroaromatic ring described ascontaining from “1 to 4 heteroatoms” means the heteroaromatic ring cancontain 1, 2, 3 or 4 heteroatoms.

[0067] When any variable (e.g., R^(a) or R^(b)) occurs more than onetime in Formula (I) or in any other formula defining an olefinicreactant suitable for use in the present invention, its definition oneach occurrence is independent of its definition at every otheroccurrence.

[0068] The term “substituted” (e.g., as in “alkyl which is optionallysubstituted with one or more substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

[0069] It is also understood that combinations of substituents and/orvariables set forth above in the formulas defining suitable olefinreactants are permissible only if such combinations result in olefinswhich are chemically stable under the conditions employed in the processof the invention and only if a stable iodohydroxylated olefin can beobtained in a detectable amount.

[0070] As stated earlier, the treatment step in the process of thepresent invention can be conducted over a wide pH range. At very low pH(e.g., less than about 1), however, the iodohydroxylation rate can bequite slow which can result in undesirably long reaction times and/orlow conversions. While not wishing to be bound by theory, thisrelatively low iodohydroxylation rate at very low pH is believed to bedue to a substantial reduction in the rate of hydrolysis of ICI and IBrto HOI. Accordingly, in one embodiment the treatment step is conductedat a pH of from about 2 to about 12 (e.g., from about 4 to about 11).The pH can be determined during the treatment step using a standard pHmonitor inserted into or otherwise in contact with the reaction mixture.

[0071] The iodohydroxylation of certain olefin reactants can bepH-sensitive, in which case the pH can be controlled by use of a bufferor by addition of acid or base. For example, olefins of Formulas (II) to(VI) and/or intermediates formed therefrom in the treatment step can beunstable under acidic conditions. Accordingly, in one embodiment, thetreatment step is conducted at a pH of from about 6 to about 12. Inanother embodiment, the treatment is conducted at a pH of from about 8to about 10 (e.g., at a pH of about 9). In an aspect of each of the twopreceding embodiments, the treatment is conducted on an olefin ofFormula (II), (III), (IV), (V), or (VI). In another aspect of each ofthese embodiments, the pH is controlled by on-demand addition of base.The role of the base is to neutralize the HCl (or HBr) generated duringthe treatment step, wherein it is believed that the HCl (HBr) generationis due to ICl (IBr) hydrolysis to HOI and that base neutralizationincreases the rate of hydrolysis to HOI. Any organic or inorganic basewhich can be used to control the pH of the reaction mixture is suitablefor use in the process of the invention. Suitable bases include thoseselected from the group consisting of alkali metal hydroxides, alkalimetal carbonates, alkali metal oxides, C₁-C₆ alkoxides of alkali metals,alkaline earth metal hydroxides, alkaline earth metal oxides, tetra(C₁-C₄ alkyl)ammonium hydroxides, and tri-(C₁-C₄ alkyl)amines. Exemplarybases include hydroxides, carbonates, and oxides of lithium, sodium andpotassium; methoxides, ethoxides, and n- and iso-propoxides of lithium,sodium, and potassium; tetramethyl- and tetraethyl-ammonium hydroxide;triethylamine; and diisopropylethylamine. In one embodiment, the base isselected from the group consisting of alkali metal hydroxides. In anaspect of the preceding embodiment, the base is NaOH or KOH.

[0072] The treatment of the olefin with aqueous iodine monohalide (i.e.,ICl or IBr) is suitably conducted at a temperature in a range of fromabout −25 to about 100° C. (e.g., from about −20 to about 95° C.), andis typically conducted at a temperature in the range of from about −10to about 85° C. The iodohydroxylation reaction can often be conductedunder relatively mild conditions. Accordingly, in one embodiment, thetemperature is in a range of from about 10 to about 50° C. In anotherembodiment, the temperature is in a range of from about 15 to about 30°C. In still another embodiment, the temperature is from about 15 toabout 25° C. (e.g., about 20° C.).

[0073] The olefin reactant is typically employed in the process of theinvention in an organic solvent. The solvent can be any organic compoundwhich under the treatment conditions employed is in the liquid phase, ischemically inert, and will dissolve, suspend, and/or disperse the olefinreactant. Particularly suitable for use in the process of the inventionis any organic solvent which is not miscible with water under theconditions employed (e.g., at a given temperature and pressure) andthereby results in a mixture comprising two phases, one of which is anorganic phase containing the olefin reactant and the other of which isan aqueous phase containing the iodine monohalide (i.e., ICl or IBr). Ifthe olefin reactant is a liquid under the selected conditions, then theolefin can alternatively be employed neat and act as both organicsolvent and substrate.

[0074] Suitable solvents include hydrocarbons, halohydrocarbons, ethers,esters, and nitriles. Typical solvents are selected from the groupconsisting of C₃-C₁₂ linear and branched alkanes, C₁-C₁₀ linear andbranched halogenated alkanes, C₅-C₁₀ cycloalkanes, C₆-C₁₄ aromatichydrocarbons, dialkyl ethers wherein each alkyl is independently a C₁-C₆alkyl, C₁-C₆ linear and branched alkanes substituted with two —O—C₁-C₆alkyl groups (which are the same or different), C₄-C₈ cyclic ethers anddiethers, C₆-C₈ aromatic ethers, C₁-C₆ alkyl esters of C₁-C₆alkylcarboxylic acids, C₁-C₁₀ alkyl alcohols, C₂-C₆ aliphatic nitriles,and C₇-C₁₀ aromatic nitriles.

[0075] In one embodiment, the solvent is selected from the groupconsisting of C₁-C₆ linear and branched halogenated alkanes, dialkylethers wherein each alkyl is independently a C₁-C₄ alkyl, C₁-C₆ linearand branched alkanes substituted with two —O—C₁-C₄ alkyl groups (whichare the same or different), C₄-C₆ cyclic ethers and diethers, C₁-C₄alkyl esters of C₁-C₆ alkylcarboxylic acids, and C₂-C₄ aliphaticnitriles. A class of organic solvents often employed in the process ofthe invention is any ester which is a C₁-C₄ alkyl ester of a C₁-C₆alkylcarboxylic acid. A sub-class of this class consists of the C₁-C₄alkyl acetates.

[0076] Exemplary solvents include pentanes (single isomers or mixturesthereof), hexanes (single isomers or mixtures), heptanes (single isomersor mixtures), and octanes (single isomers or mixtures), carbontetrachloride, chloroform, methylene chloride, 1,2-dichloroethane (DCE),1,1,2-trichloroethane (TCE), 1,1,2,2-tetrachloroethane, cyclohexane,toluene, o- and m- and p-xylene, xylene mixtures, ethylbenzene, ethylether, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), dioxane,1,2-dimethoxyethane (DME), anisole, phenetole, methyl acetate, ethylpropionate, ethyl acetate, n-propyl acetate, isopropyl acetate (IPAc),n-, t- and iso-butyl acetate, ethanol, n- and iso-propanol, tert-butylalcohol, tert-amyl alcohol, acetonitrile, propionitrile, benzonitrile,and p-tolunitrile.

[0077] As indicated above, the reaction system typically contains anorganic phase and an aqueous phase. Accordingly, in one embodiment ofthe present invention, the treatment is conducted with vigorousagitation. The term “vigorous agitation” refers herein to sufficientagitation (achieved, for example by stirring or shaking) of the mixturesuch that no phase separation can be observed visually between theaqueous and organic phases. In other words, although the aqueous andorganic phases still exist, the agitation (e.g., stirring) is sufficientso that no visible phase separation can be detected by the naked eye.

[0078] The treatment is suitably conducted at ambient pressures, butsuper-and sub-atmospheric pressures can be employed.: For example, whenthe olefin reactant is a gas under ambient conditions (e.g., lowmolecular weight alkenes such as ethylene and propylene), the treatmentcan be conducted under a pressure high enough to liquify the gas (e.g.,for use as a neat liquid, or to increase the gaseous olefin's solubilityin the organic solvent). On the other hand, an olefin reactant can beemployed as a gas, preferably with agitation sufficient to provideintimate mixing of the gas with aqueous ICl or IBr.

[0079] The iodine monohalide can be employed in any proportion withrespect to the olefin reactant which will result in the conversion of atleast some of the olefin to iodohydroxylated product. Typically,however, the iodine monohalide is employed in a proportion which willoptimize conversion of the olefin. In one embodiment, the amount ofiodine monohalide employed in the treatment step is at least about 0.5equivalent per equivalent of olefin, and is typically in the range offrom about 1 to about 10 (e.g., from about 1 to about 5) equivalents perequivalent of olefin. In another embodiment, iodine monohalide isemployed in an amount of from about 1 to about 2 (e.g., from about 1 toabout 1.8) equivalents per equivalent of olefin. In an aspect of thepreceding embodiment, the iodine monohalide is employed in an amount offrom about 1.1 to about 1.5 equivalents (e.g., from about 1.2 to about1.4 equivalents) per equivalent of olefin.

[0080] In a suitable procedure for conducting the process of the presentinvention, the olefin reactant in organic solvent is charged to areactor vessel fitted with a means for monitoring and controlling pH andtemperature, followed by addition of water and optionally a buffer.After bringing the contents of the reactor to the desired temperature,the iodine monohalide (i.e., ICl or IBr) is then added to the reactorvessel typically in the form of an aqueous solution while agitating(e.g., stirring) the reactor contents at a level sufficient to obtainintimate mixing of the organic and aqueous phases. If a basic reactionenvironment, base can be added concurrently with addition of the iodinemonohalide in order to maintain the pH at the desired level. Uponcompletion of the iodine monohalide addition, the mixture is maintainedat a suitable temperature (and optionally also maintained at a suitablepH) until the iodohydroxylation is complete or, alternatively, until adesired amount of conversion is achieved. The reaction can be quenchedby addition of a reducing agent (e.g., a dilute sodium bisulfite aqueoussolution), and the organic phase separated from the aqueous phase. Theiodohydrin product can then be recovered (i.e., isolated) from theorganic phase by conventional techniques (e.g., by chromatography, byfractional distillation to recover a liquid product, or by concentratingand/or cooling to precipitate a solid product). In the case where theiodohydrin product is an intermediate, the iodohydrin need not beisolated, but can instead be left in the organic phase or solventswitched into a different organic solvent for use in the next step ofthe synthesis.

[0081] The iodine monohalide and water can be separately added to thereactor vessel either concurrently or consecutively in either order,with subsequent formation of an aqueous iodine monohalide solution inthe reactor. Direct addition of a pre-mixed aqueous iodine monohalidesolution is preferred, however, because it eliminates an addition lineand avoids potential difficulties in metering ICl (a solid or oil withmelting point=27° C.) or IBr (solid with melting point=40° C.) into thereactor. The aqueous solution can be prepared for immediate use in theprocess of the invention simply by dissolving the desired amount of IClor IBr in water and then adding the solution into the reactor vessel. Astabilized solution of the iodine monohalide can be prepared and storedfor long periods (weeks or months) for future use in the process of theinvention. A stabilized ICl solution is a low-pH aqueous—HCl-NaClsolution. Similarly, a stabilized IBr solution is a low-pH aqueousHBr—NaBr solution. While not wishing to be bound by theory, it isbelieved that in this solution ICl, for example, exists stably andpredominantly in the form of ICl₂-(see Wang et al., J. Am. Chem. Soc.1989, 111: 7838-7844). Olefin iodohydroxylation can occur by contactingthis solution with (e.g., adding this solution to) an olefin and, ifnecessary, adjusting the pH to the basic range. The overall scheme forHOI production using the stabilized ICl solution is as follows, whereinpH control can be optionally employed in both steps:

[0082] The iodine monohalide can suitably be added all at once at thestart, or intermittently or continuously as the iodohydroxylationproceeds. Intermittent or continuous addition of iodine monohalide ispreferred. The monohalide (ICl or IBr) is suitably added to the mixtureat a rate of from about 0.2 to about 30 equivalents of iodine monohalideper equivalent of olefin per hour, and is typically added at a rate offrom about 0.3 to about 10 equivalents (e.g., 0.5 to 5 equivalents) perequivalent of olefin per hour. In one embodiment, the iodine monohalideaddition is continuous until the desired total amount of ICl or IBr hasbeen charged to the reaction mixture. In an aspect of this embodiment,the iodine monohalide is added continuously at a rate of from about 0.5to 5 equivalents per equivalent of olefin per hour. In another aspect ofthis embodiment, the iodine monohalide is added continuously at a rateof from about 0.5 to 2 equivalents (e.g., from about 1 to about 1.8equivalents) per equivalent of olefin per hour.

[0083] The treatment time can vary widely depending upon, inter alia,the temperature, the choice of olefin reactant, and the relative amountsof iodine monohalide and olefin, but it is typically in the range offrom about 0.05 to about 24 hours.

[0084] If desired, the progress of the iodohydroxylation can be followedby monitoring the disappearance of the olefin and/or the appearance ofthe iodohydrin product using TLC, HPLC, NMR or GC.

[0085] The present invention also includes a process for preparing aniodohydrin of Formula (VII):

[0086] which comprises treating an olefin of Formula (II):

[0087] in an organic solvent with an aqueous solution of an iodinemonohalide at a pH in a range of from about 6 to about 12 to obtainiodohydrin VII, wherein:

[0088] the iodine monohalide selected from iodine monochloride andiodine monobromide;

[0089] and wherein in Formulas (II) and (VII):

[0090] A is absent, CH₂, O, or S;

[0091] R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or HetB;wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB is optionallysubstituted with one or more substituents (e.g., from 1 to 4, or 1 to 3,or 1 or 2 substituents; or is mono-substituted) each of which isindependently halogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or—O—C₁-C₆ haloalkyl;

[0092] HetB in R⁵ is a 5- or 6-membered monocyclic aromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and

[0093] R⁶ and R⁷ are each independently —H, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₃-C₆ cycloalkyl, or aryl, wherein aryl is selected fromphenyl and naphthyl, and is optionally substituted with one or moresubstituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents; oris mono-substituted) each of which is independently halogen, —OH, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; oralternatively

[0094] R⁶ and R⁷ together with the carbons to which each is attachedform a fused benzene ring which is optionally substituted with one ormore substituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents;or is mono-substituted) each of which is independently halogen, —OH,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl.

[0095] Embodiments of this process include the process as just describedincorporating one or more of the features (a), (b), (c), (d), (e), (f1)or (f2), and (g) as follows:

[0096] (a) the treatment is conducted at a pH of from about 7 to about10 (or from about 8 to about 10);

[0097] (b) the pH of the mixture is controlled by on-demand addition ofbase (e.g., an alkali metal hydroxide such as NaOH);

[0098] (c) the treatment is conducted at a temperature in a range offrom about −10 to about 85° C. (or from about 10 to about 50° C, or fromabout 15 to about 30° C.);

[0099] (d) the iodine monohalide (e.g., ICl) is employed in an amount offrom about 1 to about 5 equivalents (or from about 1 to about 2equivalents, or from about 1 to about 1.8 equivalents) per equivalent ofolefin II;

[0100] (e) the treatment is conducted with vigorous agitation;

[0101] (f1) the organic solvent is selected from the group consisting ofC₁-C₆ linear and branched halogenated alkanes, dialkyl ethers whereineach alkyl is independently a C₁-C₄ alkyl, C₁-C₆ linear and branchedalkanes substituted with two —O—C₁-C₄ alkyl groups (which are the sameor different), C₄-C₆ cyclic ethers and diethers, C₁-C₄ alkyl esters ofC₁-C₆ alkylcarboxylic acids, and C₂-C₄ aliphatic nitrites;

[0102] (f2) the organic solvent is a C₁-C₄ alkyl acetate (e.g., IPAc);and

[0103] (g) the olefin is:

[0104] wherein:

[0105] R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or HetB;wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB is optionallysubstituted with one or more substituents (e.g., from 1 to 4, or 1 to 3,or 1 or 2 substituents; or is mono-substituted) each of which isindependently halogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or—O—C₁-C₆ haloalkyl;

[0106] HetB in R⁵ is a 5- or 6-membered monocyclic aromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and

[0107] R⁶ is —H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl, orphenyl, wherein the phenyl is optionally substituted with one or moresubstituents (e.g., from 1 to 4, or 1 to 3, or 1 or 2 substituents; oris mono-substituted) each of which is independently halogen, —OH, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl;

[0108] each Y* is independently —H, halogen, —C₁-C₄ alkyl, —C₁-C₄fluoroalkyl, or —O—C₁-C₄ alkyl; and

[0109] p* is an integer equal to zero, 1 or 2.

[0110] The present invention also includes a process for preparingiodohydrin 2 or 4:

[0111] which comprises treating olefin 1 or 3:

[0112] in an organic solvent with an aqueous solution of iodinemonohalide at a pH in a range of from about 6 to about 12 to obtainiodohydrin 2 or 4; wherein the iodine monohalide is ICl or IBr.

[0113] Olefin 1 (also referred to in the art as an allyl acetonide) canbe prepared as described in Example 1 of U.S. Pat. No. 5,728,840. Olefin(or allyl acetonide) 3 can be prepared as described in Example 1 of WO01/38332.

[0114] Embodiments of this process include the process as just describedincorporating one or more of the features (a), (b), (c), (d), (e), and(f1) or (f2) set forth above.

[0115] Still other embodiments of the present invention include theprocess as originally defined and described above and any embodiments oraspects thereof as heretofore defined and described, further comprisingisolating (alternatively referred to as recovering) the iodohydrinproduct from the treatment mixture. Iodohydrins of Formula (VH) areuseful as intermediates in the preparation of HIV protease inhibitors asmay be seen by reference to U.S. application Ser. No. 09/718,223 (filedNov. 21, 2000) and to WO 01/38332, the disclosures of which are hereinincorporated by reference in its entireties. More particularly,iodohydrin 2 can be converted into indinavir as described in U.S. Pat.No. 5,728,840 (see, e.g., Examples 1 to 8), and iodohydrin 4 can be usedas an intermediate in the preparation of a series of HIV proteaseinhibitors as described in U.S. Ser. No. 09/718,223 and WO 01/38332(see, e.g., Example 1 and subsequent examples). The following schemedepicts the preparation of indinavir via iodohydrin 2:

[0116] The terms “iodohydroxylated olefin” and “iodohydrin” are usedherein interchangeably.

[0117] As used herein, the term “C₁₋₂₀ alkyl” (or “C₁-C₂₀ alkyl”) meanslinear or branched chain alkyl groups having from 1 to 20 carbon atoms.The term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means linear or branched chainalkyl groups having from 1 to 6 carbon atoms and includes all of thehexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. Similar terms such as“C₁₋₁₀ alkyl” and “C₁₋₄ alkyl” have analogous meanings.

[0118] The term “C₂₋₂₀ alkenyl” (or “C₂-C₂₀ alkenyl”) means linear orbranched chain alkenyl groups having from 2 to 20 carbon atoms. The term“C₂₋₁₀ alkenyl” has an analogous meaning and includes all of thedecenyl, nonenyl, octenyl, heptenyl, hexenyl and pentenyl isomers aswell as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl,2-propenyl, and ethenyl (or vinyl). Similar terms such as “C₂₋₆ alkenyl”have an analogous meaning.

[0119] The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclicring of an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). Similar terms such as “C₃₋₆ cycloalkyl” have an analogousmeaning.

[0120] The term “C₅₋₁₀ cycloalkenyl” (or “C₅-C₁₀ cycloalkenyl”) means acyclic ring of an alkene having five to ten total carbon atoms (i.e.,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,or cyclodecenyl). Similar terms such as “C₅₋₈ cycloalkenyl” have ananalogous meaning.

[0121] The term “C₅₋₁₀ cycloalkadienyl” (or “C₅-C₁₀ cycloalkadienyl”)means a cyclic ring of an alkadiene having five to ten total carbonatoms (i.e., cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, cyclononadienyl, or cyclodecadienyl).

[0122] The term “halogen” (or “halo”) refers to fluorine, chlorine,bromine and iodine (alternatively referred to as fluoro, chloro, bromo,and iodo).

[0123] The term “C₁₋₆ haloalkyl” (which may alternatively be referred toas “C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆linear or branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₄ fluoroalkyl” (which may alternatively be referred to as“C₁-C₄ fluoroalkyl” or “fluorinated C₁-C₄ alkyl”) has an analogousmeaning except that the halogen substituents are restricted to fluoro.Suitable fluoroalkyls include the series (CH₂)₀₋₃CF₃.

[0124] The term “aryl” as used herein refers to any ring which is (i) anaromatic carbocyclic ring optionally substituted with 1 or 2 otheraromatic carbocyclic rings or (ii) an aromatic carbocyclic fused ringsystem optionally substituted with 1 or 2 aromatic carbocyclic rings.The fused ring system contains two or more carbocyclic rings in whicheach ring shares two adjacent carbon atoms with at least one other ring.A subset of aryl groups particularly suitable for defining olefinreactants employed in the process of the invention includes thoseselected from phenyl, biphenyl, naphthyl, anthryl, and phenanthryl.Another particularly suitable subset of aryl groups is phenyl andnaphthyl. Still another particularly suitable subset is phenyl per se.

[0125] The term “heterocycle” refers to any ring which is (i) a 4- to8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to12-membered bicyclic ring system, or (iii) an 11 to 16-memberedtricyclic ring system; wherein each ring in (ii) or (iii) is independentof or fused to the other ring or rings and each ring is saturated orunsaturated; and wherein the monocyclic ring, bicyclic ring system, ortricyclic ring system contains from 1 to 6 heteroatoms independentlyselected from N, O and S.

[0126] A subset of heterocycles suitable for defining olefin reactantsemployed in the process of the invention includes the set of saturatedheterocyclic rings. The term “saturated heterocyclic ring” refers to a4- to 7-membered saturated monocyclic ring which contains one or moreheteroatoms independently selected from N, O and S. Representativeexamples include piperidinyl, piperazinyl, azepanyl (i.e.,

[0127] ), pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, tetrahydrothienyl, tetrahydrofuryl (ortetrahydrofuranyl), thiazinanyl (e.g., 1,2-thiazinanyl

[0128] ), thiadiazinanyl (e.g., 1,2,6-thiadiazinanyl

[0129] ), and dioxanyl.

[0130] Heteroaromatic rings form another subset of the heterocycles thatis suitable for defining olefin reactants of the present invention. Theterm “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromaticring containing one or more (e.g., from 1 to 4) heteroatomsindependently selected from N, O and S. Representative examples ofheteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, and thiadiazolyl.

[0131] Representative examples of bicyclic heterocycles includebenzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl,quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl,tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl(i.e.,

[0132] ), and benzo-1,3-dioxolyl (i.e.,

[0133] ).

[0134] Representative examples of tricyclic heterocycles includephenothiazinyl, carbazolyl, beta-carbolinyl, tetrahydro-beta-carbolinyl,acridinyl, phenazinyl, and phenoxazinyl.

[0135] The following examples serve only to illustrate the invention andits practice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 1 Iodohydroxylation of Allyl Acetonide 1 Using ICl

[0136]

[0137] Run A:

[0138] The iodohydroxylation of 1 was carried out in a Mettler RC-1reaction calorimeter (reactor volume: 1L), which provides computercontrol over the pH and dosing control functions. To the top chargeopening in the reactor was added 200 mL of allyl acetonide 1 in IPAchaving an assay of 148 g/L (0.082 mole), followed by the addition of 121mL of DI water and 0.45 g of NaHCO₃. The reactor stirrer was set to 800rpm (which provided vigorous agitation as defined herein), and thereactor temperature adjusted to 20° C. while purging the system withnitrogen. A pH control probe was inserted into the reactor, and thesystem was purged with nitrogen to ensure removal of air. To the reactorwas then added 1.2 equivalents (18.9 mL ) of 5.2 M ICl solution over atime interval of 60 minutes. (Note: The ICl solution (5.2 M) wasprepared by dissolving ICl (50.6 g), a solution of concentrated HCl (2.9g; 37% aqueous), and NaCl (14.02 g) in distilled water (20 mL). Thesolution was then diluted to a total volume of 60 mL with distilledwater.) The ICl solution was added using a syringe pump at an additionrate of 0.31 mL/min. NaOH (1M) was added concurrently with the additionof the ICl at a rate such that the reactor contents were maintained at apH of 9.0. The NaOH addition was performed by the control loop of theMettler RC-1 computerized system. The reaction was continued for aperiod of 10 minutes after complete addition of the ICl solution. LCanalysis showed 100% conversion of 1 and with a 95% yield of iodohydrin2.

[0139] Run B:

[0140] A second iodohydroxylation of 1 was conducted using the samereactor, procedure and conditions described in Run A, except that thereactor stirrer was operated at 1500 rpm (which provided vigorousagitation as defined herein). LC analysis of a grab sample 10 min aftercomplete addition of the ICl solution showed 100% conversion of 1 with a95% yield of iodohydrin 2.

EXAMPLE 2 Iodohydroxylation of Allyl Acetonide 3 Using ICl

[0141]

[0142] The iodohydroxylation of 3 was conducted using the Mettler RC-1reaction calorimeter described in Example 1. 200 mL of allyl acetonide 3in IPAc having an assay of 109 g/L (0.058 mole) were added to the topcharge opening in the reactor, followed by the addition of 121 mL of DIwater and 0.45 g of NaHCO₃. The reactor stirrer was set to 800 rpm(which provided vigorous agitation as defined herein) and the reactortemperature was adjusted to 20° C. while purging the system withnitrogen. A pH control probe was inserted into the reactor and thesystem was purged with nitrogen to ensure removal of air. To the reactorwas then added 1.2 equivalents (13.3 mL ) of 5.2 M ICl solution over atime interval of 60 minutes. The ICl solution was added using a syringepump at an addition rate of 0.22 mL/min. NaOH (1M) was addedconcurrently with the addition of the ICl at a rate such that thereactor contents were maintained at a pH of 9.0. The NaOH addition wasperformed by the control loop of the Mettler RC-1 computerized system.The reaction was continued for a period of 10 minutes after completeaddition of the ICl solutions. LC analysis showed 100% conversion of 3and greater than 90% yield of iodohydrin 4.

EXAMPLE 3 Iodohydroxylation of Allyl Acetonide 1 Using NaOCl/NaI

[0143] Run A:

[0144] The iodohydroxylation of allyl acetonide 1 via NaOCl/NaI wasconducted in the reactor system described in Example 1 as follows: Allylacetonide 1 in IPAc (200 mL; 148 g/L (=0.082 mole)) was added to the topcharge opening in the reactor, followed by the addition of 121 mL of DIwater and 0.45 g of NaHCO₃. The reactor stirrer was set at 800 rpm(which provided vigorous agitation as defined herein), and the reactortemperature adjusted to 20° C. A pH control probe was inserted into thereactor. To the reactor was added 2.0 equivalents (76.3 g) of 16 wt. %aqueous sodium hypochlorite solution and 1.8 equivalents (34.41 g, 22.82mL) of 57% aqueous Nal solution over 60 minutes. The NaI solution wasadded using a syringe pump at an addition rate of 0.380 mL/min. TheNaOCl solution was added by means of a diaphragm pump, adjusted toprovide a uniform addition rate. Concurrent with the addition of theNaOCl and NaI solutions, H₂SO₄ was added using the control loop of theMettler RC-1 system at a rate such that the reactor contents weremaintained at a pH of 9.0. LC analysis of a grab sample 10 min after thecompleting the addition of the NaOCl and NaI solutions showed 100%conversion of acetonide 1 and a 95% yield of iodohydrin 2.

[0145] Run B:

[0146] A second iodohydroxylation of 1 using NaOCl/NaI was conductedusing the same reactor, procedure and conditions as described in Run A,except that the reactor stirrer was operated at 1500 rpm (which providedvigorous agitation as defined herein). LC analysis of a grab sample 10minutes after complete addition of the NaOCl and NaI solutions showed75% conversion of 1 and a 71% yield of iodohydrin 2.

[0147] Table 1 below presents the percent conversions of allyl acetonide1 to iodohydrin 2 obtained in Examples 1 and 3 as a function of reactorstirrer speed. The stirrer speed is a measure of the degree of agitationand mixing of the reaction mixture. The results show that the NaOCl/NaIprocess exhibits a mixing sensitivity which is absent in the IClprocess. These results indicate that the ICl process of the invention ismore scaleable than the NaOCI/NaI process, which is a significantprocess advantage. TABLE 1 Stirring Speed % Yield Example No. Process(rpm) % Conversion) 1-A IC1 800 95 (100) 1-B ″ 1500 95 (100) 3-ANaOCl/NaI 800 95 (100) 3-B ″ 1500 71 (75) 

[0148] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, the practice of the invention encompasses all of the usualvariations, adaptations and/or modifications that come within the scopeof the following claims.

What is claimed is:
 1. A process for preparing an iodohydroxylatedolefin which comprises treating an olefin with an aqueous solution of aniodine monohalide selected from iodine monochloride and iodinemonobromide.
 2. The process according to claim 1, wherein the treatmentis conducted at a temperature in a range of from about −25 to about 100°C.
 3. The process according to claim 1, wherein the olefin is employedas a neat liquid or in an organic solvent.
 4. The process according toclaim 3, wherein the olefin is in an organic solvent selected from thegroup consisting of hydrocarbons, halohydrocarbons, ethers, esters, andnitriles.
 5. The process according to claim 3, wherein the treatment isconducted with vigorous agitation.
 6. The process according to claim 1,wherein the iodine monohalide is employed in an amount of from about 1to about 10 equivalents per equivalent of olefin.
 7. The processaccording to claim 1, wherein the pH is in a range of from about 2 toabout
 12. 8. The process according to claim 7, wherein the pH is in arange of from about 6 to about
 12. 9. The process according to claim 8,wherein the pH is controlled by on-demand addition of base.
 10. Theprocess according to claim 1, wherein the aqueous solution of iodinemonohalide is added at a rate of from about 0.2 to about 30 equivalentsof iodine monohalide per equivalent of olefin per hour.
 11. The processaccording to claim 1, wherein the olefin is of Formula (I):

wherein each of R¹, R², R³ and R⁴ is independently: (1) —H, (2)—CO₂R^(a), (3) —C(═O)R^(a), (4) —C(═O)N(R^(a)R^(b)), (5) —CN, (6) C₁₋₂₀alkyl, (7) C₂₋₂₀ alkenyl, (8) C₃₋₈ cycloalkyl, (9) C₅₋₈ cycloalkenyl,(10) aryl, or (11) heterocycle, (12) C₁₋₂₀ alkyl substituted with from 1to 3 substituents each of which is independently C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, aryl, or heterocycle, (13) C₂₋₂₀ alkenyl substituted withfrom 1 to 3 substituents each of which is independently C₃₋₈ cycloalkyl,C₅₋₈ cycloalkenyl, aryl, or heterocycle, (14) C₁₋₂₀ alkyl substitutedwith —C(═O)-aryl or —C(═O)-heterocycle, or (15) C₂₋₂₀ alkenylsubstituted with —C(═O)-aryl or —C(═O)-heterocycle; wherein the alkyl in(6) or (12) or (14) or the alkenyl in (7) or (13) or (15) is optionallysubstituted with one or more substituents each of which is independentlyhalogen, —OH, —CN, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —S(O)_(n)R^(a), N(R_(a)R^(b)), —C(═O)N(R^(a)R^(b)),N(R^(a))C(═O)—N(R^(a)R^(b)), —C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)),N(R^(a))—C(═O)—C₁₋₆ alkyl-N(R^(a)R^(b)), —N(R^(a))SO₂R^(b), or—SO₂N(R^(a)R^(b)); wherein the cycloalkyl in (8) or (12) or (13), thecycloalkenyl (9) or (12) or (13), or the aryl in (10) or (12) or (13) or(14) or (15) is optionally substituted with one or more substituentseach of which is independently halogen, —OH, —CN, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),—S(O)_(n)R^(a), —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)—C₁₋₆alkyl-N(R^(a)R^(b)), phenyl, —C₁₋₆ alkyl-phenyl, HetA, or —C₁₋₆alkyl—HetA; and wherein the heterocycle (11) or (12) or (13) or (14) or(15) is optionally substituted with one or more substituents each ofwhich is independently halogen, —OH, —CN, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl,—O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),—S(O)_(n)R^(a), —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)—C₁₋₆alkyl-N(R^(a)R^(b)), phenyl, —C₁₋₆ alkyl-phenyl, —C₃₋₈ cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, or oxo; or alternatively R¹ and R³ are eachindependently as defined above, and R² and R⁴ together with each of thecarbon atoms of the carbon-carbon double bond form C₅₋₁₀ cycloalkenyl orC₅₋₁₀ cycloalkadienyl, either of which is optionally substituted withone or more substituents each of which is independently halogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy; oralternatively R¹ and R² are each independently as defined above, and R³and R⁴ together with the carbon atom of the carbon-carbon double bond towhich they are both attached form C₅₋₁₀ cycloalkyl or C₅₋₁₀cycloalkenyl, either of which is optionally substituted with one or moresubstituents each of which is independently halogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy each aryl isindependently (i) an aromatic carbocyclic ring optionally substitutedwith 1 or 2 other aromatic carbocyclic rings or (ii) an aromaticcarbocyclic fused ring system optionally substituted with 1 or 2aromatic carbocyclic rings; each heterocycle is independently (i) a 4-to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to12-membered bicyclic ring system, or (iii) an 11 to 16-memberedtricyclic ring system; wherein each ring in (ii) or (iii) is independentof or fused to the other ring or rings and each ring is saturated orunsaturated; and wherein the monocyclic ring, bicyclic ring system, ortricyclic ring system contains from 1 to 6 heteroatoms independentlyselected from N, O and S; each HetA is independently: (i) a 4- to7-membered saturated heterocyclic ring containing from 1 to 4 heteratomsselected from N, O and S, wherein the saturated heterocyclic ring isoptionally substituted with from 1 to 3 substituents each of which isindependently halogen, —C₁₋₄ alkyl, or oxo, or (ii) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl; each n is an integerindependently equal to zero, 1 or 2; and each R^(a) and R^(b) isindependently —H or —C₁₋₆ alkyl.
 12. The process according to claim 1,wherein the olefin is of Formula (II):

wherein A is absent, CH₂, O, or S; R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, or HetB; wherein the alkyl, cycloalkyl, phenyl,naphthyl, or HetB is optionally substituted with one or moresubstituents each of which is independently halogen, hydroxy, —C₁-C₆haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; HetB in R⁵ is a 5- or6-membered monocyclic aromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S; and R⁶ and R⁷ are eachindependently —H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl, oraryl, wherein aryl is selected from phenyl and naphthyl, and isoptionally substituted with one or more substituents each of which isindependently halogen, —OH, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆alkyl, or —O—C₁-C₆ haloalkyl; or alternatively R⁶ and R⁷ together withthe carbons to which each is attached form a fused benzene ring which isoptionally substituted with one or more substituents each of which isindependently halogen, —OH, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆alkyl, or —O—C₁-C₆ haloalkyl.
 13. The process according to claim 12wherein the olefin is:

wherein: R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or HetB;wherein the alkyl, cycloalkyl, phenyl; naphthyl, or HetB is optionallysubstituted with one or more substituents each of which is independentlyhalogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆haloalkyl; HetB in R⁵ is a 5- or 6-membered monocyclic aromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and R⁶ is —H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl, orphenyl, wherein the phenyl is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; each Y* isindependently —H, halogen, —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, or —O—C₁-C₄alkyl; and p* is an integer equal to zero, 1 or
 2. 14. The processaccording to claim 13, wherein the olefin is

and the obtained iodohydroxylated olefin is


15. The process according to claim 12, wherein the pH is in a range offrom about 6 to about
 12. 16. A process for preparing an iodohydrin ofFormula (VII):

which comprises treating an olefin of Formula (II):

in an organic solvent with an aqueous solution of an iodine monohalideat a pH in a range of from about 6 to about 12 to obtain iodohydrin VII,wherein: the iodine monohalide selected from iodine monochloride andiodine monobromide; and wherein in Formulas (II) and (VII): A is absent,CH₂, O, or S; R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, orHetB; wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB isoptionally substituted with one or more substituents each of which isindependently halogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or—O—C₁-C₆ haloalkyl; HetB in R⁵ is a 5- or 6-membered monocyclic aromaticring containing from 1 to 4 heteroatoms independently selected from N, Oand S; and R⁶ and R⁷ are each independently —H, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₃-C₆ cycloalkyl, or aryl, wherein aryl is selected fromphenyl and naphthyl, and is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; oralternatively R⁶ and R⁷ together with the carbons to which each isattached form a fused benzene ring which is optionally substituted withone or more substituents each of which is independently halogen, —OH,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl.17. The process according to claim 16, wherein the treatment isconducted at a temperature in a range of from about −10 to about 85° C.18. The process according to claim 16, wherein the iodine monohalide isemployed in an amount of from about 1 to about 5 equivalents perequivalent of olefin II.
 19. The process according to claim 16, whereinthe treatment is conducted with vigorous agitation.
 20. The processaccording to claim 16, wherein the pH is controlled by on-demandaddition of base.
 21. The process according to claim 16, wherein theorganic solvent is selected from the group consisting of C₁-C₆ linearand branched halogenated alkanes, dialkyl ethers wherein each alkyl isindependently a C₁-C₄ alkyl, C₁-C₆ linear and branched alkanessubstituted with two —O—C₁-C₄ alkyl groups (which are the same ordifferent), C₄-C₆ cyclic ethers and diethers, C₁-C₄ alkyl esters ofC₁-C₆ alkylcarboxylic acids, and C₂-C₄ aliphatic nitrites.
 22. Theprocess according to claim 16, wherein the olefin is:

wherein: R⁵ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, or HetB;wherein the alkyl, cycloalkyl, phenyl, naphthyl, or HetB is optionallysubstituted with one or more substituents each of which is independentlyhalogen, hydroxy, —C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆haloalkyl; HetB in R⁵ is a 5- or 6-membered monocyclic aromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS; and R⁶ is —H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl, orphenyl, wherein the phenyl is optionally substituted with one or moresubstituents each of which is independently halogen, —OH, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —O—C₁-C₆ alkyl, or —O—C₁-C₆ haloalkyl; each Y* isindependently —H, halogen, —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, or —O—C₁-C₄alkyl; and p* is an integer equal to zero, 1 or
 2. 23. The processaccording to claim 22, wherein: the treatment is conducted at atemperature in a range of from about −10 to about 85° C.; the iodinemonohalide is iodine monochloride employed in an amount of from about 1to about 5 equivalents per equivalent of the olefin; the treatment isconducted with vigorous agitation; and the solvent is selected from thegroup consisting of C₁-C₆ linear and branched halogenated alkanes,dialkyl ethers wherein each alkyl is independently a C₁-C₄ alkyl, C₁-C₆linear and branched alkanes substituted with two —O—C₁-C₄ alkyl groups(which are the same or different), C₄-C₆ cyclic ethers and diethers,C₁-C₄ alkyl esters of C₁-C₆ alkylcarboxylic acids, and C₂-C₄ aliphaticnitrites.
 24. The process according to claim 23, wherein the olefin is


25. The process according to claim 24, wherein: the treatment isconducted at a pH of from about 7 to about 10; the treatment isconducted at a temperature in a range of from about 10 to about 50° C.;the iodine monochloride is employed in an amount of from about 1 toabout 1.8 equivalents per equivalent of the olefin; and the solvent is aC₁-C₄ alkyl acetate.